Cisplatin-induced Kidney Injury Research Articles

Amelioration of Cisplatin-Induced Kidney Injury by Pometia pinnata

Introduction: Cisplatin is one of the most effective anticancer drugs. But using cisplatin can cause very serious nephrotoxicity and acute kidney injury (AKI). Pometia pinnata (PE) or commonly referred to as matoa is a typical plant, especially Papua, Indonesia. Pometia pinnata belongs to the Sapindaceae family. This study aimed to determined the nephroprotective activity of the extract ethanol pometia pinnata on rats induced cisplatin. Methods: 30 rats are divided into six groups, each group were contained 5 rats. Group I was a normal group which rats only given CMC (carboxy methyl celluloce). Group II was a negative group which rats injected 7 mg / kgbw of Cisplatin in day 3. Group III was a positive group which rats given vitamin C 1% from day 1 to 7 and in day 3 rats were injected cisplatin. Group IV-VI were extract groups (100 mg / kgbb, 200 mg / kgb, 400 mg / kgbb) which rats orally given extract from day 1 to 7 and in day 3 rats were injected cisplatin. On day 8 rats were injected ketamine 1% which directly took the blood from the heart. Results: The result shows that EEPE on rats biochemical parameters including urea, creatinine, uric acid. Group II showed that there was a significant increase (p <0.05) compared to the normal group that was not given cisplatin and extracts. Whereas in the group given the extract in groups IV, V, and VI there was a reduction in biochemical parameters because the Pometia leaf extract had high antioxidant activity so that it had nephroprotective activity. extract ethanol pometia pinnata can reduced the level of sodium, potassium and chloride of each group after receiving cisplatin. Statistically group II that only given cisplatin has significantly different with group I (p<0,05) and also statically different with group VI (p<0,05).

Mitochondrial Superoxide Dismutase in Cisplatin-Induced Kidney Injury.

Cisplatin is a chemotherapy agent commonly used to treat a wide variety of cancers. Despite the potential for both severe acute and chronic side effects, it remains a preferred therapeutic option for many malignancies due to its potent anti-tumor activity. Common cisplatin-associated side-effects include acute kidney injury (AKI) and chronic kidney disease (CKD). These renal injuries may cause delays and potentially cessation of cisplatin therapy and have long-term effects on renal function reserve. Thus, developing mechanism-based interventional strategies that minimize cisplatin-associated kidney injury without reducing efficacy would be of great benefit. In addition to its action of cross-linking DNA, cisplatin has been shown to affect mitochondrial metabolism, resulting in mitochondrially derived reactive oxygen species (ROS). Increased ROS formation in renal proximal convoluted tubule cells is associated with cisplatin-induced AKI and CKD. We review the mechanisms by which cisplatin may induce AKI and CKD and discuss the potential of mitochondrial superoxide dismutase mimetics to prevent platinum-associated nephrotoxicity.

Ginsenoside Rg3 attenuates cisplatin-induced kidney injury through inhibition of apoptosis and autophagy-inhibited NLRP3.

The NOD-like receptor family pyrin domain-containing (NLRP3) inflammasomes is centrally implicated in cisplatin (CP)-induced kidney injury. Autophagy is critical for inhibiting production of NLRP3 protein that effectively reduces the inflammatory response. Ginsenoside Rg3 (SY), an active component extracted from ginseng, is reported to protect against CP-induced nephrotoxicity. However, the mechanisms underlying renoprotection by SY have not been established to date. Our results indicate that SY attenuated CP-induced apoptosis and damage in vivo and in vitro, as evidenced by increased cell viability, decreased the proportion of late apoptotic cells, elevated mitochondrial membrane potential, and ameliorated histopathological damage of the kidney. SY ameliorated CP-induced human renal tubular (HK-2) cells and kidney injury through upregulation of LC3II/I and beclin-1, inhibition of p62, NLRP3, ASC, caspase-1, and interleukin-1β. However, blockade of autophagy by 3-methyladenine reversed the suppression of SY on NLRP3 inflammasome activation and the protection of SY on HK-2 cells. Our collective results support the utility of SY as a therapeutic agent that effectively protects against CP-induced kidney injury by activating the autophagy-mediated NLRP3 inhibition pathway.

Potential Therapeutic Targets for Cisplatin-Induced Kidney Injury: Lessons from Other Models of AKI and Fibrosis.

The effectiveness of cisplatin, a mainstay in treatment of many solid organ cancers, is hindered by dose-limiting nephrotoxicity. Cisplatin causes acute kidney injury (AKI) in 30% of patients. Patients who do not develop AKI by clinical standards during the course of treatment are still at risk for long-term decline in kidney function and the development of chronic kidney disease (CKD). The connection between AKI and CKD has become increasingly studied, with renal fibrosis being a hallmark of CKD development. To prevent both the short- and long-term effects of cisplatin, researchers must use models that reflect both types of pathology. Although a lot is known about cisplatin-induced AKI, very little is known about the mechanisms by which repeated low levels of cisplatin lead to fibrosis development. In this review, strategies used in various rodent models to prevent kidney injury, its progression to fibrosis, or both are examined to gain mechanistic insights and identify potential therapeutic targets for cisplatin-induced kidney pathologies. Reviewing the results from these models highlights the diverse and highly complex role of cell death, cell senescence, endoplasmic reticulum stress, autophagy, and immune cell activation in acute and chronic kidney injuries. Use of several models of kidney injury is needed for development of agents that will prevent all aspects of cisplatin-induced kidney injury.

A NIR fluorescent probe for Vanin-1 and its applications in imaging, kidney injury diagnosis, and the development of inhibitor

Vanin-1 is an amidohydrolase that catalyses the conversion of pantetheine into the amino-thiol cysteamine and pantothenic acid (coenzyme A precursor), which plays a vital role in multiple physiological and pathological processes. In this study, an enzyme-activated near-infrared (NIR) fluorescent probe (DDAV) has been constructed for sensitively detecting Vanin-1 activity in complicated biosamples on the basis of its catalytic characteristics. DDAV exhibited a high selectivity and sensitivity toward Vanin-1 and was successfully applied to the early diagnosis of kidney injury in cisplatin-induced kidney injury model. In addition, DDAV could serve as a visual tool for in situ imaging endogenous Vanin-1 in vivo. More importantly, Enterococcus faecalis 20247 which possessed high expression of Vanin-1 was screened out from intestinal bacteria using DDAV, provided useful guidance for the rational use of NSAIDs in clinic. Finally, oleuropein as a potent natural inhibitor for Vanin-1 was discovered from herbal medicines library using a high-throughput screening method using DDAV, which held great promise for clinical therapy of inflammatory bowel disease.

PPAR-δ activation reduces cisplatin-induced apoptosis via inhibiting p53/Bax/caspase-3 pathway without modulating autophagy in murine renal proximal tubular cells.

Cisplatin-induced injury of renal proximal tubular cells results basically from increased apoptosis via mitochondrial damage, and is mitigated by appropriate enhancement of autophagy. Peroxisome proliferator-activated receptor-delta (PPAR-δ) reportedly protects against not only mitochondrial damages but also enhances autophagy. Thus, PPAR-δ may protect against cisplatin-induced kidney injury. We examined the protective effects of PPAR-δ activation on cisplatin-induced cellular injury and their detailed mechanisms in a murine renal proximal tubular (mProx) cell line using GW0742, an authentic PPAR-δ activator. Cisplatin-induced cell damages were evaluated by TUNEL assay and immunoblot analyses for p53, 14-3-3, Bax, Bcl2, cytochrome C, and activated caspases. Autophagy status was examined by immunoblot analyses for p62 and LC3. GW0742 suppressed cisplatin-induced apoptosis of mProx cells by reducing the activation of caspase-3 via attenuating the phosphorylation of p53 and 14-3-3, mitochondrial Bax accumulation, cytochrome C release from mitochondria to the cytosol and ensuing cytosolic caspase-9 activation. In contrast, GW0742 did not diminish cisplatin-enhanced activation of caspases-8 or -12 as extrinsic or endothelium reticulum apoptotic pathways, respectively. The inhibitory effect of GW0742 on cisplatin-induced caspase-3 activation was significantly diminished by silencing of the PPAR-δ gene expression. GW0742 itself had no influence on starvation-stimulated or cisplatin-induced autophagy in mProx cells, suggesting that the protective effects were not mediated by autophagy modification. Our results indicate that GW0742 may serve as a candidate agent to mitigate cisplatin nephrotoxicity via inhibiting the mitochondrial apoptotic pathway considerably depending on PPAR-δ, without modulating autophagy.

Borassus flabellifer L. crude male flower extracts alleviate cisplatin-induced oxidative stress in rat kidney cells

Objective: To investigate the effects of Borassus flabellifer L. extracts on antioxidant activity, maintenance of cellular redox, and mitochondrial function in cisplatin-induced kidney injury. Methods: The extracts of Borassus flabellifer were obtained from crude male flowers using ethyl acetate and methanol. The antioxidant potential was evaluated by 2,2-azino-bis-(3-ethylbenzothiazoline- 6-sulfonic acid), 2,2-diphenyl-1-picrylhydrazyl, and ferric reducing antioxidant power, and total phenolic content was also determined. Cytoprotective activity of ethyl acetate and methanolic extracts was assessed after kidney cells were treated with cisplatin. Oxidative stress was determined by glutathione (GSH) assay, and formation of reactive oxygen species (ROS) and changes in mitochondrial transmembrane potential (ΔΨm) using 2’,7’-dichlorofluorescin diacetate and JC-10 assays, respectively. Results: Borassus flabellifer methanolic extract exhibited greater antioxidant activity than the ethyl acetate extract. Cytoprotective effect was demonstrated in both extracts, particularly in the ethyl acetate extract. The extracts showed protection against the cytotoxic effect of cisplatin by prevention of the increased GSSG and declined GSH/GSSG ratio. Both extracts also prevented the increase in ROS formation, and loss of ΔΨm. Conclusions: Both Borassus flabellifer extracts show antioxidant activity and cytoprotective effect against cisplatin-induced cytotoxicity of NRK-52E cells by preventing oxidative stress and maintenance of GSH redox status. Borassus flabellifer extracts may possess beneficial effects on the prevention of oxidative stress- induced cell injury.

Smad3-Targeted Therapy Protects against Cisplatin-Induced AKI by Attenuating Programmed Cell Death and Inflammation via a NOX4-Dependent Mechanism

Background: Transforming growth factor-β (TGF-β)/Smad signaling is the central mediator in renal fibrosis, yet its functional role in acute kidney injury (AKI) is not fully understood. Recent evidence showed that TGF-β/Smad3 may be involved in the pathogenesis of AKI, but its functional role and mechanism of action in cisplatin-induced AKI are unclear. Objectives: Demonstrating that Smad3 may play certain roles in cisplatin nephropathy due to its potential effect on programmed cell death and inflammation. Methods: Here, we established a cisplatin-induced AKI mouse model with Smad3 knockout mice and created stable in vitro models with Smad3 knockdown tubular epithelial cells. In addition, we tested the potential of Smad3-targeted therapy using 2 in vivo protocols – lentivirus-mediated Smad3 silencing in vivo and use of naringenin, a monomer used in traditional Chinese medicine and a natural inhibitor of Smad3. Results: Disruption of Smad3 attenuated cisplatin-induced kidney injury, inflammation, and NADPH oxidase 4-dependent oxidative stress. We found that Smad3-targeted therapy protected against loss of renal function and alleviated apoptosis, RIPK-mediated necroptosis, renal inflammation, and oxidative stress in cisplatin nephropathy. Conclusions: These findings show that Smad3 promotes cisplatin-induced AKI and Smad3-targeted therapy protects against this pathological process. These findings have substantial clinical relevance, as they suggest a therapeutic target for AKI.

The effects of carvedilol, metoprolol and propranolol on cisplatin-induced kidney injury

The β-adrenoceptor blockers may have anti-oxidant properties or induce β-arrestin recruitment beyond classical desensitization of receptor/G protein coupling, offering potential therapeutic benefits. Here, we investigated the effects of carvedilol, metoprolol and propranolol in an animal model of cisplatin-induced nephrotoxicity. Rats received the β-blockers (3 or 12 mg/kg/day) with or without cisplatin, and kidney function was investigated using renal scintigraphy, histopathology, and serum variables. Metoprolol and propranolol as well as low-dose carvedilol did not alter kidney function, per se. Meanwhile, high-dose carvedilol reduced renal accumulation of Technetium-99m (99mTc)–labeled dimercaptosuccinic acid (99mTc-DMSA) without significant effect on other variables. Furthermore, low-dose carvedilol prevented cisplatin-induced reduction of tracer uptake, but high-dose of this drug aggravated the situation. In this regard, both low and high -doses of carvedilol significantly inhibited cisplatin effects on kidney histology, BUN and creatinine levels. Also, high-dose propranolol inhibited cisplatin adverse effects on radiotracer uptake, histological manifestations, BUN and creatinine levels, while metoprolol failed to cause a notable effect. Taken together, carvedilol and high-dose propranolol may offer potential benefits in cisplatin nephrotoxicity.

Nephroprotective effect of ethanol extract and fractions of a sea lettuce, Ulva fasciata against cisplatin-induced kidney injury in rats.

Cisplatin is widely used in anticancer therapy, but a substantial percentage of patients who receive the therapeutic dose of cisplatin develop nephrotoxicity. Hepatotoxicity may also develop after a single dose or low repeated doses of cisplatin. Ulva fasciata is an edible seaweed, commonly known as sea lettuces have also been shown various biological activities. In this study, ethanol extract and its solvent fractions (n-hexane and chloroform) of U. fasciata were given (orally) to different groups of rats for 10 days. Injury to the kidney was induced by administrating cisplatin, intraperitoneally (i.p.) to rats at a dose of 7 mg/kg body weight (b.w.) dissolved in 1 mL saline, at 5th day of the experiment. At 10th day rats were sacrificed and kidney parameters (creatinine, urea, and blood urea nitrogen (BUN)) and electrolyte balance (Ca++, Mg++, K+, and Na+) in serum were determined, while oxidative stress markers glutathione (GSH), catalase (CAT) and malondialdehyde (MDA), and inflammatory cytokines, tumor necrosis factor (TNF α), and interleukin (IL-6) were determined in kidney tissues. Histological examination of the kidney was also performed to examine the changes in kidney tissues. Cisplatin caused adverse effects on blood parameters, antioxidants, and inflammatory markers with severe renal tubular injury in kidney tissues. Ethanol extract of U. fasciata and its fractions effectively improved these disorders and diminished the renal dysfunction. However, ethanol extract was found more effective in attenuating the adverse effect of cisplatin than its fractions. n-Hexane-soluble fraction that was subjected to GC-FID and GC-MS analysis revealed the presence of several compounds and some of them are new from this source. It could be concluded that the U. fasciata possesses nephroprotective effect and can attenuate cisplatin-induced renal dysfunction. Since U. fasciata is an edible seaweed, it may be used as a diet supplement.

AMP-activated protein kinase contributes to cisplatin-induced renal epithelial cell apoptosis and acute kidney injury.

Cisplatin, a commonly used anticancer drug, has been shown to induce acute kidney injury, which limits its clinical use in cancer treatment. Emerging evidence has suggested that AMP-activated protein kinase (AMPK), which functions as a cellular energy sensor, is activated by various cellular stresses that deplete cellular ATP. However, the potential role of AMPK in cisplatin-induced apoptosis of renal tubular epithelial cells has not been studied. In this study, we demonstrated that cisplatin activates AMPK (Thr172 phosphorylation) in cultured renal tubular epithelial cells in a time-dependent manner, which was associated with p53 phosphorylation. Compound C, a selective AMPK inhibitor, suppressed cisplatin-induced AMPK activation, p53 phosphorylation, Bax induction, and caspase 3 activation. Furthermore, silencing AMPK expression by siRNA attenuated cisplatin-induced p53 phosphorylation, Bax induction, and caspase 3 activation. In a mouse model of cisplatin-induced kidney injury, compound C inhibited p53 phosphorylation, Bax expression, caspase 3 activation, and apoptosis, protecting the kidney from injury and dysfunction. Taken together, these results suggest that the AMPK-p53-Bax signaling pathway plays a crucial role in cisplatin-induced tubular epithelial cell apoptosis.

LIGHT deficiency aggravates cisplatin-induced acute kidney injury by upregulating mitochondrial apoptosis

Cisplatin is widely used as a chemotherapeutic agent for treating patients with solid tumors. The most common side effect of cisplatin treatment is nephrotoxicity. Recent studies have shown that mitochondrial apoptotic pathways are involved in cisplatin-induced acute kidney injury (Cis-AKI). LIGHT, the 14th member of the tumor necrosis factor superfamily (TNFSF14), was found to induce apoptosis of certain types of tumor cells. So far, a link between LIGHT and Cis-AKI has not been reported. In this study, we observed that expression of LIGHT and its receptors HVEM and LTβR was increased in kidney tissues of mice after cisplatin treatment. LIGHT deficiency aggravated kidney injury, as evidenced by more severe tubular injury; remarkably increased levels of serum creatinine (Scr), blood urea nitrogen (BUN), and both kidney injury molecule-1 (KIM-1) and inflammatory cytokine mRNAs in renal tissues. Moreover, in the renal tissues of LIGHT KO mice, cisplatin-induced mitochondrion injury and the levels of the pro-apoptotic molecules Bax, Cytochrome C (Cyt C), cleaved caspase-3, and cleaved caspase-9 were dramatically increased; in contrast, the expression of anti-apoptotic molecule Bcl-2 was markedly reduced, compared to those in WT mice, suggesting that LIGHT deficiency accelerated cisplatin-induced mitochondrial apoptosis of renal tubular cells in these mice. Accordingly, treatment with recombinant human LIGHT (rLIGHT) was shown to alleviate cisplatin-induced kidney injury in vivo. Similar results were observed after the human renal tubular epithelial cell line HK-2 cells exposure to rLIGHT stimulation, evidenced by the reduction in the mitochondrion dysfunction (as confirmed by the significant reduced oxidative stress and membrane potential changes) and in the percentage of cells apoptosis. While blocking LIGHT with the soluble fusion protein LTβR-Ig or HVEM-Ig accelerated the HK-2 cells apoptosis. In conclusion, LIGHT deficiency aggravates Cis-AKI by promoting mitochondrial apoptosis pathways.

Curcumin Prevents Epithelial-to Mesenchymal Transition-Mediated Ovarian Cancer Progression through NRF2/ETBR/ET-1 Axis and Preserves Mitochondria Biogenesis in Kidney after Cisplatin Administration.

Purpose: Ovarian carcinoma is one of the gynaecological malignancies that have the highest mortality rates due to its progressivity. Endothelin signalling plays a leading role in the progression of ovarian cancer through Epithelial-to-Mesenchymal Transition (EMT). Cisplatin commonly used as potent chemotherapy; however, its application hindered by its nephrotoxic effect. Curcumin, a turmeric-derived compound, has an anticancer property, as well as a renal protective effect. Moreover, curcumin augments the affinity of the antioxidant enzyme, while inhibits endothelin-1 (ET-1) signalling. The effects of curcumin on ovarian cancer progression and cisplatin-induced kidney injury remain unknown. Methods: Curcumin was used as a supplementary therapy together with cisplatin in Human Ovarian Cancer Cell line (SKOV3) and also in rodent-induced ovarian cancer. The kidney phenotype in the ovarian cancer rat model after cisplatin ± curcumin administration will also be analyzed Results: Co-treatment of cisplatin with curcumin enhanced the expression of a gene involved in apoptosis in association with NRF2 enhancement, thus activated ETBR-mediated ET-1 clearance in SKOV3 cell and ovarian cancer model in rat. Moreover, curcumin treatment improved mitochondria biogenesis markers such as PGC-1α and TFAM and prevented the elevated of ET-1-mediated renal fibrosis and apoptosis in kidney isolated from cisplatin-treated ovarian cancer rat. Conclusion: Curcumin could be potentially added as an anticancer adjuvant with protective effects in the kidney; thus, improves the efficacy and safety of cisplatin treatment in the clinical setting.

Vagus nerve stimulation even after injury ameliorates cisplatin-induced nephropathy via reducing macrophage infiltration

The efficacy of prior activation of an anti-inflammatory pathway called the cholinergic anti-inflammatory pathway (CAP) through vagus nerve stimulation (VNS) has been reported in renal ischemia-reperfusion injury models. However, there have been no reports that have demonstrated the effectiveness of VNS after injury. We investigated the renoprotective effect of VNS in a cisplatin-induced nephropathy model. C57BL/6 mice were injected with cisplatin, and VNS was conducted 24 hours later. Kidney function, histology, and a kidney injury marker (Kim-1) were evaluated 72 hours after cisplatin administration. To further explore the role of the spleen and splenic macrophages, key players in the CAP, splenectomy, and adoptive transfer of macrophages treated with the selective α7 nicotinic acetylcholine receptor agonist GTS-21 were conducted. VNS treatment significantly suppressed cisplatin-induced kidney injury. This effect was abolished by splenectomy, while adoptive transfer of GTS-21-treated macrophages improved renal outcomes. VNS also reduced the expression of cytokines and chemokines, including CCL2, which is a potent chemokine attracting monocytes/macrophages, accompanied by a decline in the number of infiltrating macrophages. Taken together, stimulation of the CAP protected the kidney even after injury in a cisplatin-induced nephropathy model. Considering the feasibility and anti-inflammatory effects of VNS, the findings suggest that VNS may be a promising therapeutic tool for acute kidney injury.

Omeprazole attenuates cisplatin-induced kidney injury through suppression of the TLR4/NF-κB/NLRP3 signaling pathway

Renal toxicity is the primary factor that limits clinical use of cisplatin (CP). A previous study showed that omeprazole (OME) protected against CP-induced toxicity in human renal tubular HK-2 cells and rat kidneys. However, the protective mechanisms of OME have not been characterized. We evaluated the ability of OME to inhibit CP-induced inflammation, and characterized the pathways responsible for this effect. Rats were randomly divided into five groups (n = 10/group). The OME groups were intraperitoneally injected with 1.8 or 3.6 mg OME /kg body weight once daily for 5 days. One hour after final administration of vehicle or OME, all rats (except those in control group and OME alone group) were intraperitoneally injected with 15 mg/kg CP. Twenty-four hours after CP injection, the surgery was applied. The time points and dosing of OME and CP were calculated based on previous studies and the therapeutic dose for patients. Omeprazole attenuated CP-induced apoptosis and damage in vivo and in vitro, as evidenced by increased cell viability and prevention of structural damage. Omeprazole ameliorated CP-induced renal injury through inhibition of NF-κB activation and IκBα degradation, and down-regulation of toll-like receptor 4 (TLR4) and Nod-like receptor protein 3 (NLRP3). Lipopolysaccharide, a TLR4 agonist, was used to verify this mechanism. The results indicated that OME inhibited CP-induced expression of inflammatory proteins, and this effect was blunted by co-treatment with LPS in HK-2 cells. These findings suggested that the protective effects of OME against CP-induced kidney damage may occur through inhibition of the TLR4/NF-κB/NLRP3 signaling pathway. This study provided evidence that OME may be a promising agent to inhibit CP-induced nephrotoxicity.

Isovitexin protects against cisplatin-induced kidney injury in mice through inhibiting inflammatory and oxidative responses

In this study, we investigated the renoprotective effects and mechanism of isovitexin, a glycosylflavonoid isolated from rice hulls of Oryza sativa, against cisplatin-induced kidney injury in mice. The mice were treated with cisplatin for four consecutive days and at the second day, the mice were received with isovitexin for three consecutive days. The levels of blood urea nitrogen (BUN) and creatinine in serum and the levels of MDA, ROS, TNF-α, IL-1ß and IL-6 in kidney tissues were measured. The proteins of Nrf2 and NF-κB signaling pathways were measured by western blot analysis. Our results demonstrated that isovitexin inhibited CP-induced increases in serum BUN and creatinine. Isovitexin inhibited CP-induced inflammation by inhibiting TNF-α, IL-1ß and IL-6 production in kidney tissues. Also, isovitexin inhibited CP-induced oxidative stress by inhibiting MDA and ROS production. Furthermore, isovitexin was found to inhibit CP-induced NF-κB activation and increase Nrf2 and HO-1 expression. In conclusion, our results indicated that isovitexin protected against CP-induced kidney injury by suppressing inflammatory and oxidative responses.

SIRT1 Mediates Effects of FGF21 to Ameliorate Cisplatin-Induced Acute Kidney Injury.

Acute kidney injury (AKI) is a common complication in cancer patients. Kidney function is closely related to patients’ quality of life and tumor prognosis. Cisplatin is a highly effective anti-tumor drug. However, the use of cisplatin is limited by its nephrotoxicity. It has been reported that FGF21 has a renal-protective function, but the mechanisms by which it does so remain unclear. In this study, we show that the expression of FGF21 is significantly upregulated in both in vitro and in vivo cisplatin-induced AKI models. Administration of recombinant FGF21 to cisplatin-induced AKI mice resulted in significantly decreased blood urea nitrogen (BUN) and serum creatinine levels, as well as significantly reduced protein levels of kidney injury molecule-1 (TIM-1), C-caspase 3, and Bax. H&E-stained kidney sections from cisplatin-induced AKI mice treated with recombinant FGF21 showed a relatively normal renal tissue structure, a reduced number of necrotic sites and vacuolar changes, and decreased casts, suggesting alleviated renal tubular injury. Experiments with an AKI cell model (cisplatin-treated HK-2 cells) yielded similar results as the mouse model; recombinant FGF21 significantly downregulated protein expression levels of TIM-1, C-caspase 3, and Bax. Furthermore, administration of recombinant FGF21 to cisplatin-treated AKI models significantly increased SIRT1 expression, and the beneficial effects of FGF21 on kidney injury were reversed by SIRT1 knockdown. Collectively, our results suggest that SIRT1 mediates the protective effect of FGF21 on cisplatin-induced kidney injury.

Dnmt3a and Dnmt3b-Decommissioned Fetal Enhancers are Linked to Kidney Disease.

Cytosine methylation is an epigenetic mark that dictates cell fate and response to stimuli. The timing and establishment of methylation logic during kidney development remains unknown. DNA methyltransferase 3a and 3b are the enzymes capable of establishing de novo methylation. We generated mice with genetic deletion of Dnmt3a and Dnmt3b in nephron progenitor cells (Six2CreDnmt3a/3b) and kidney tubule cells (KspCreDnmt3a/3b). We characterized KspCreDnmt3a/3b mice at baseline and after injury. Unbiased omics profiling, such as whole genome bisulfite sequencing, reduced representation bisulfite sequencing and RNA sequencing were performed on whole-kidney samples and isolated renal tubule cells. KspCreDnmt3a/3b mice showed no obvious morphologic and functional alterations at baseline. Knockout animals exhibited increased resistance to cisplatin-induced kidney injury, but not to folic acid-induced fibrosis. Whole-genome bisulfite sequencing indicated that Dnmt3a and Dnmt3b play an important role in methylation of gene regulatory regions that act as fetal-specific enhancers in the developing kidney but are decommissioned in the mature kidney. Loss of Dnmt3a and Dnmt3b resulted in failure to silence developmental genes. We also found that fetal-enhancer regions methylated by Dnmt3a and Dnmt3b were enriched for kidney disease genetic risk loci. Methylation patterns of kidneys from patients with CKD showed defects similar to those in mice with Dnmt3a and Dnmt3b deletion. Our results indicate a potential locus-specific convergence of genetic, epigenetic, and developmental elements in kidney disease development.

SUN-030 A SMALL MOLECULE FROM GANODERMA LUCIDUM PROTECTS AGAINST CISPLATIN-INDUCED KIDNEY INJURY VIA SUPPRESSING NLRP3/CASPASE-1 RELATED PYROPTOSIS

Ganoderma lucidum (Lingzhi) is the medicinal fungi traditionally used to promote health and longevity. Previous studies indicate the Ganoderma lucidum potentially boosts the immune system and suppresses the inflammation in vivo and in vitro. Pyroptosis is a highly inflammatory form of programmed cell death. The study aimed to screen molecules against cisplatin-induced kidney injury. Forty-two molecules were isolated from Ganoderma lucidum and tested by the cell viability assay for screening protective effects. The mouse tubular epithelial cells (mTECs) were pre-treated with small molecules (20-60 µM) for 6 hours, followed by adding cisplatin (25 µM) for 24-48 hours. The molecular mechanisms of attenuating the cisplatin-induced kidney injury were further examined. Among 42 molecules, cell viability tests showed that six molecules significantly attenuated cisplatin-induced cytotoxicity in mTECs (p<0.0001). Molecular docking predicted qNFLZ may interact with an upstream protein of the NFκB pathway. The real-time PCR analysis showed that qNFLZ significantly reduced IL-1β and MCP-1. The western-blot analysis indicated qNFLZ suppressed the phosphorylation of NFκB P65, and activation of NLRP3, caspase-1 and Gasdermin D. The findings suggested qNFLZ protects against cisplatin-induced kidney injury via suppressing NLRP3-caspase-1-Gasdermin D pathway. The study demonstrates qNFLZ is a potential molecule to protect against cisplatin-induced kidney injury clinically.

Bisdemethoxycurcumin attenuates cisplatin-induced renal injury through anti-apoptosis, anti-oxidant and anti-inflammatory

Cisplatin is a widely used chemotherapy drug that is first-line therapy for a variety of tumors. Unfortunately, its adverse effects on various normal tissues and organs, especially nephrotoxicity, threaten the life of patients. Although the mechanism of cisplatin nephrotoxicity has been confirmed to be related to oxidative stress, apoptosis of renal tubular epithelial cells and inflammatory response, there is no effective prevention strategy in the clinic. Here, we found that bisdemethoxycurcumin (BDMC), a natural compound, can significantly attenuates cisplatin-induced apoptosis of renal tubular epithelial cells in vitro at the concentration of 5–20 μM and has a significant protective effect on cisplatin-induced kidney injury in mice at the dose of 50 mg/kg. Mechanistically, BDMC attenuates cisplatin-induced apoptosis of renal tubular epithelial cells by inhibiting cisplatin-induced up-regulation of p53. Meanwhile, BDMC counteracts oxidative stress by inhibiting cisplatin-induced down-regulation of nuclear factor erythroid-2-related factor 2 (Nrf2). BDMC also significantly reduced the expression of intercellular adhesion molecule-1 (ICAM-1) and monocyte chemoattractant protein-1 (MCP-1) proteins, as well as the expression and translocation of the p65 subunit of nuclear factor-κB (NF-κB p65) into the nucleus, all of which were increased in the kidney by cisplatin treatment. Collectively, BDMC might be an effective prevention strategy which could against cisplatin-induced nephrotoxicity, and our research may shed a new light on treatment of drug toxicity.